Felix A. Conte

Endocrine and neurologic outcome in childhood craniopharyngioma: Review of effect of treatment in 42 patients

Forty-two cases of craniopharyngioma in children reviewed. Only 9.5% had sought medical attention because of symptoms suggesting hormonal deficit; however, growth retardation was present in 53% and growth hormone deficiency was documented in 72% before treatment. Multiple hypothalamic-pituitary hormone deficiencies were present in all patients after treatment. Eleven percent had normal skull radiographs at presentation; pneumonencephalograms and computed tomographic brain scans were abnormal on every occasion on which they were performed. Recurrence and mortality rates as well as the neurologic outcome of survivors were similar in children treated by radical excision and those treated by limited excision plus radiotherapy. The neurologic prognosis was poorest in those children who had limited excision or drainage without radiotherapy. Additional hypothalamic-pituitary dysfunction following treatment was less common in children who had limited excision plus radiotherapy than in children who had either limited excision or attempted total removal. Unless gross total tumor excision can be readily achieved, limited excision by transsphenoidal microsurgery or craniotomy plus radiotherapy appears to be the treatment of choice for craniopharyngioma in childhood.

Summary of Consensus Statement on Intersex Disorders and Their Management

Advances in understanding of genetic control of sexual determination and differentiation, improvements in diagnostic testing and surgical genital repair, and the persistent controversies inherent to clinical management were all compelling factors that led to the organization of an international consensus conference. The goals were to acknowledge and discuss the more controversial issues in intersex management, provide management guidelines for intersex patients, and identify and prioritize questions that need additional investigation. This is a summary statement. Advances in molecular genetic causes of abnormal sexual development and heightened awareness of the ethical and patient-advocacy issues mandate reexamination of existing nomenclature for patients with intersex.1 Terminology such as “pseudohermaphroditism” is controversial, potentially pejorative to patients,2 and inherently confusing. Therefore, the term “disorders of sex development” (DSD) is proposed to indicate congenital conditions with atypical development of chromosomal, gonadal, or anatomic sex. Additional rationale for new classification is the need for modern categorization to integrate the modern molecular genetic aspects, to maximize precision when applying definitions and diagnostic labels,3 and to meet the need for psychologically sensitive yet descriptive medical terminology. Nomenclature should be flexible enough to incorporate new information, robust enough to maintain a consistent framework, use descriptive terms, reflect genetic etiology, accommodate phenotypic variation spectrum, and be useful for clinicians, scientists, patients, and families. Hence, we propose a new classification (see “Consensus Statement on Management of Intersex Disorders”4 in this months issue of Pediatrics Electronic Edition ). Three traditionally conceptualized domains of psychosexual development are gender identity (ones self-representation [ie, male or female]), gender role (sexually dimorphic behaviors within the general population, such as toy preferences, aggression, and spatial ability), and sexual orientation (direction[s] of erotic interest). Gender dissatisfaction denotes unhappiness with assigned sex and may result in gender self-reassignment. Psychosexual developmental factors relate to parental psychopathology, parent-child … Address correspondence to Peter A. Lee, MD, PhD, Department of Pediatrics, MC-H085, Penn State College of Medicine, Milton S. Hershey Medical Center, Box 850, 500 University Dr, Hershey, PA 17033-0850. E-mail: plee{at}psu.edu

CONGENITAL ADRENAL HYPERPLASIA DUE TO DEFICIENT CHOLESTEROL SIDE‐CHAIN CLEAVAGE ACTIVITY (20, 22‐DESMOLASE) IN A PATIENT TREATED FOR 18 YEARS

Two siblings, a 9‐week‐old female and an 18‐year‐old male pseudohermaphrodite are described with deficient cholesterol side‐chain cleavage activity. The female died untreated in 1954; the second sibling, a phenotypically female infant with 46 XY karyotype, was diagnosed at age 5 weeks. Massive adrenal hyperplasia was revealed by intravenous pyelography showing downward displacement of the kidneys. Secretion rates of cortisol, aldosterone, deoxycor‐ticosterone and corticosterone were unmeasurable. Urinary 17‐hydroxycorti‐costeroids (17‐OHCS), tetrahydrocortisol, 17‐ketosteroids (17‐KS), pregnanetriol, pregnanediol, and Δ5‐3β‐ol steroids were not detected during prolonged administration of ACTH. Plasma concentrations and urinary excretion of gonadotrophins were increased. Gonadal mitochondria did not convert radioloabelled cholesterol to pregnenolone. The gluccocorticoid and mineralo‐corticoid deficiencies have been controlled well by steroid replacement therapy. Plasma ACTH concentrations and plasma renin activity remained strikingly elevated even when supraphysiologic doses of glucocorticoids and mineralocor‐ticoids were given. Oestrogen replacement alone induced a pubertal growth spurt. The differential diagnosis, the effects of long‐term steroid replacement therapy, and comparison with previously reported findings are discussed.

Treatment of Cushing's Disease in Childhood and Adolescence by Transsphenoidal Microadenomectomy

Fifteen unselected children and adolescents with Cushings disease were treated by transsphenoidal exploration and microadenomectomy. In only three patients was radiographic examination of the sella turcica, including computed tomography, useful in indicating the presence and location of a pituitary microadenoma. Transsphenoidal microadenomectomy corrected hypercortisolism in 14 of the 15 patients; no adenoma was detected in one patient, and one required a second operation six months after the first because of incomplete removal of the adenoma. All 14 lost weight and cushingoid stigmata and had normal or catch-up growth (if epiphyses were not fused) and progression of puberty. In one patient, a recurrence was successfully treated by repeat microadenomectomy six years after the first procedure. The low morbidity and failure rate of the procedure, the low recurrence rate, the rapid amelioration of signs of hypercortisolism, and the preservation of pituitary function in the present study support transsphenoidal microadenomectomy as a low-risk approach to the initial treatment of Cushings disease in childhood and adolescence.

Congenital hypogonadotropic hypogonadism and micropenis: effect of testosterone treatment on adult penile size why sex reversal is not indicated.

Micropenis is commonly due to fetal testosterone deficiency. The clinical management of this form of micropenis has been contentious, with disagreement about the capacity of testosterone treatment to induce a functionally adequate adult penis. As a consequence, some clinicians recommend sex reversal of affected male infants. We studied 8 male subjects with micropenis secondary to congenital pituitary gonadotropin deficiency from infancy or childhood to maturity (ages 18 to 27 years). Four patients were treated with testosterone before 2 years of age (group I) and four between age 6 and 13 years (group II). At presentation, the mean penile length in group I was 1.1 cm (-4 SD; range, 0.5 to 1.5 cm) and in group II it was 2.7 cm (-3.4 SD; range, 1.5 to 3.5 cm). All patients received one or more courses of 3 intramuscular injections of testosterone enanthate (25 or 50 mg) at 4-week intervals in infancy or childhood. At the age of puberty the dose was gradually increased to 200 mg monthly and later to an adult replacement regimen. As adults, both group I and II had attained a mean final penile length of 10.3 cm 2.7 cm with a range of 8 to 14 cm (mean adult stretched penile length for Caucasians is 12.4 2.7 cm). Six of 8 men were sexually active, and all reported normal male gender identity and psychosocial behavior. We conclude that 1 or 2 short courses of testosterone therapy in infancy and childhood augment penile size into the normal range for age in boys with micropenis secondary to fetal testosterone deficiency; replacement therapy at the age of puberty results in an adult size penis within 2 SD of the mean. We found no clinical, psychologic, or physiologic indications to support conversion of affected male infants to girls. Further, the results of this study do not support the notion, derived from data in the rat, that testosterone treatment in infancy or childhood impairs penile growth in adolescence and compromises adult penile length.

Delayed onset of hypopituitarism: Sequelae of therapeutic irradiation of central nervous system, eye, and middle ear tumors†‡

Four children with short stature who received irradiation to the head in conventional doses had clinical and laboratory evidence of hypothalamic-pituitary hormone deficiencies several years later. Growth hormone was deficient in all. One patient also had evidence of TSH, ACTH, and gonadotropin deficiency. Basal prolactin levels and prolactin response to synthetic TRF were normal in all patients tested. Treatment with human growth hormone significantly increased growth rate. We suggest that children should have the hypothalamic-pituitary area shielded from irradiation. Periodic measurements of hypothalamic-pituitary function should be performed in children who have had irradiation to the head, in order to detect and treat hormonal deficiencies before growth and development are seriously compromised.

Growth and Growth Hormone: I. changes in Serum Level of Growth Hormone Following Hypoglycemia in 134 children with Growth Rctardation

Extract: The change in levels of growth hormone in serum (SGH) following insulin-induced hypoglycemia was evaluated in 134 prepubertal children with growth retardation and 10 control subjects with normal growth patterns by radioimmunoassay, utilizing 131I-HGH and rabbit antiserum to human growth hormone. Mean maximum growth hormone concentration (mμg/ml) at any time during the test was:Among factors found to affect the SGH response to insulin-induced hypoglycemia were: a) elevated fasting concentration of SGH which appeared to alter the responsiveness to stimulation; and b) age.The mean maximum SGH concentration of the control subjects following insulin-induced hypoglycemia was 12.4 mμg/ml.In 52/53 patients with hypopituitarism, the SGH concentration was 1 mμg or less at rest, with no increase or an increase to a maximum of 2.5 mμg/ml following hypoglycemia. One patient (CL) had a fasting serum growth hormone (FSCH) concentration of 3.4 mμg/ml with a rise to 5 mμg/ml at 60 minutes, as indicated in tables II and IIa.Clinical data on 20 patients with constitutional shortness of stature are presented in table III. The mean maximum GH concentration following insulin-induced hypoglycemia of this group was 12.5 mμg/ml, a value comparable to that obtained in the control subjects (table IIIa).Clinical data, including growth rate, of patients with primordial dwarfism are presented in table IV. The mean maximum SGH concentration following hypoglycemia of the 22 patients in this grop was 12.1 mμg/ml (table IVa). This response was not significantly different from that observed in the control group.Nine patients with XO gonadal dysgenesis had a mean maximum SGH response to hypoglycemia of 13.4 mμg/ml, as indicated in tables VI and VIa.Five children with delayed adolescence had a mean maximum SGH response of 11.8 mμg/ml, as shown in tables VI and VIa.Four of five infants with maternal deprivation included in this study showed evidence of increased insulin sensitivity, but the mean maximum SGH response was not significantly different from that of the control group. Clinical data on nine patients with psychosocial drawfism are presented in table VI. The nine children in this group had a mean maximal rise of SGH concentration to 10.9 mμg/ml. Two of the children had an abnormal SGH response with concentrations of 1 mμg/ml in the fasting specimen and no rise following hypoglycemia. RS, who was retested after a hospitalization period of two months, had a maximum SGH rise to 7.4 mμg/ml (table VIa).Clinical data on 11 patients with a variety of diseases associated with their growth retardation are presented in table VII. Included in this group are two males, NF and MB, with blunted responses to insulin-induced hypoglycemia and in whom the diagnosis of partial GH deficiency cannot be excluded.As indicated on figures 1a and 1b, the mean maximum SGH response to insulin-induced hypoglycemia in children with growth retardation was not significantly different from the response observed in the control group. There was, however, a highly significant difference in the response of the control group when compared to the group of children with hypopituitarism.In the presence of an elevated SGH concentration, eight of the eighteen subjects showed a decrease in FGH concentration or no response following insulin-induced hypoglycemia. This was observed in four control subjects and four children with growth retardation. The level of FSGH was significantly higher in children less than four years of age, but there was no significant correlation of the level of FSGH with age in children over four years, or according to sex. In this study, there was no correlation demonstrated between a decrease of 40% or greater in blood glucose and the maximum GH response achieved.The response to therapy with human pituitary growth hormone (HGH) was evaluated in 8 children with growth retardation who had a mean maximum SGH concentration of 12.0 mμg/ml. In six of the patients, none of whom had the clinical features of pituitary dwarfism, there was no significant change in the rate of growth during the period of administration of HGH. Three of the six patients subsequently had low levels of antibodies to HGH and three had no detectable antibodies. ER, a primordial dwarf, had an acceleration in his growth rate during the first period of treatment with HGH which was not sustained. An increase in growth rate to 6.9cm/yr was observed in the second patient (NF) suspected of having mild or partial GH deficiency. In contrast, 20 patients with SGH levels of less than 2 mμg/ml had a growth rate of 9 to 15 cm/yr on treatment with HGH.No evidence of a GH deficiency or a defect in the responsiveness of the hypothalamic GH-releasing mechanism was demonstrated in children with growth disorders, including constitutional shortness of stature, primordial dwarfism and gonadal dysgenesis. On the basis of our data, a FSGH of 7 mμg/ml or an increase to 7 mμg/ml or more folowing insulin-induced hypoglycemia has a high probability of association with normal pituitary acidophile function. A rigid definition of the normal range of SGH respons to hypoglycemia cannot be established because, in a small proportion of instances, there is overlap between the normal subject and some GH-deficient patients.Problems in the interpretation of the rsponse to insulin-induced hypoglycemia have been observed. In children who have a borderline rise of SGH of 3 to 5 mμg/ml, the response may be indicative of GH deficiency. In a few children, however, individual differences in responsiveness to various stimuli have been observed. It is suggested that GH stimulation tests with arginine infusion or vasopressin administration be used in a child who exhibits a blunted GH response to hypoglycemia. In some children who have an apparently normal serum ‘immunoreactive’ GH response to a provocative test despite physical stigmata of hypopituitarism, short-term therapy with HGH may be necessary to establish the diagnosis of GH insufficiency.Speculation: It has been observed that the changes in SGH induced by hypoglycemia are less in children than in adults. This difference between children and adults may be related to the concentration in serum of testosterone or estrogen, an altered sensitivity of the hypothalamus to stimuli in children, or to age related variations in the secretory rate of the pituitary. SGH response to insulin-induced hypoglycemia has been valuable in distinguishing children with GH deficiency, especially when this occurs as an isolated defect, from children with other forms of growth retardation. It has not been useful in identifying the etiology of growth retardation from other causes.

Pediatric Endocrinology Update: An Overview

The goals of this presentation are to review the essential roles of aromatase, estrogens and the estrogen receptor in pubertal growth. Estrogen deficiency due to mutations in the aromatase gene (CYP19) and estrogen resistance due to disruptive mutations in the estrogen receptor gene have no effect on normal male sexual maturation in puberty. However, they lead to absence of the pubertal growth spurt, delayed bone maturation, unfused epiphyses, continued growth into adulthood and very tall adult stature in both sexes. Gonadotropin and androgen levels are elevated in patients with either estrogen deficiency (aromatase deficiency) or estrogen resistance (estrogen receptor mutation). Glucose intolerance, hyperinsulinemia and lipid abnormalities are also present. Skeletal integrity is compromised. Increased bone turnover, reduced bone mineral density and osteoporosis develop in both sexes. Sexual orientation is appropriate in males and females. In females, aromatase deficiency in the ovary causes pubertal virilization and multicystic ovaries because of elevated gonadotropins and androgens. Simultaneously, secondary sexual maturation fails to occur. Placental aromatase deficiency results in virilization of the mother and her female fetus because of the accumulation of potent androgens which are not converted to estrogens. The male fetus has normal genitalia. In conclusion, estrogens are essential for normal female secondary sexual maturation, bone maturation, epiphyseal fusion, pubertal growth spurt and achievement of normal bone mineral mass. Estrogens also influence insulin sensitivity and lipid homeostasis. However, estrogens do not appear to be essential for fetal survival, placental growth, or female sexual differentiation.

Responsivity of Pituitary Gonadotropes to Luteinizing Hormone-releasing Factor in Idiopathic Precocious Puberty, Precocious Thelarche, Precocious Adrenarche, and in Patients Treated with Medroxyprogesterone Acetate

Extract: One hundred micrograms synthetic luteinizing hormone-releasing factor (LRF) were administered to 13 girls and 2 boys with idiopathic precocious puberty, 3 girls with precocious thelarche, 2 girls with precocious adrenarche, and 5 children treated with medroxyprogesterone acetate (MPA). Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex steroid responses were assessed.The mean readily releasable LH rose to a peak of 8.4 ± 1.8 ng/ml (LER 960) in the children with idiopathic precocious puberty and was significantly greater than in normal prepubertal (1.8 ± 0.14) or pubertal children (4.9 ± 0.34). The peak plasma FSH response (8.4 ± 1.4 ng/ml) (LER 869) was higher in precocious puberty but not significantly greater than in normal prepubertal (5.3 ± 1.9) or pubertal girls (6.0 ± 1.2). The mean concentration of plasma estradiol rose significantly above resting levels after LRF in the girls with idiopathic precocious puberty. The LH response in girls with precocious thelarche and adrenarche was in the prepubertal range. In 4 of 5 children with sexual precocity treated with MPA, the LH release evoked by LRF was diminished.Speculation: Premature neural activation of hypothalamic LRF synthesis and release may occur in children with idiopathic precocious puberty. This leads to increased pituitary gonadotropin synthesis, storage, and more readily releasable LH. The higher FSH release after LRF in normal girls than boys may be a factor in the strikingly higher prevalence of idiopathic precocious puberty in girls than in boys.

Pseudotumor Cerebri Associated with Initiation of Levothyroxine Therapy for Juvenile Hypothyroidism

Pseudotumor CEREBRI (benign intracranial hypertension), a syndrome characterized by increased intracranial pressure without focal neurologic dysfunction, occurs in association with a variety of end...